Based on previous observations that acute hypoxemia, which enhances nitric oxide (NO) production, depresses the activation of group IV afferents after repetitive low-frequency muscle stimulation (MS), we hypothesized that endogenous NO modulates the response of these nerve endings to their specific stimuli. The present study in rabbits examined the effects of a blocker of NO synthase (NG-nitro-L-arginine methyl ester L, L-NAME) and an exogenous NO donor (3-morpholinosydnonimine, SIN-1) on the group IV afferents of tibialis anterior. The efficacy of the two test agents was judged by their effects on systemic blood pressure. L-NAME markedly elevated (+46%) the resting discharge rate of group IV afferents but abolished their activation after repetitive MS. After SIN-1 injection, there was a transient decrease in blood pressure, which correlated well with a lowered resting discharge rate of group IV afferents. SIN-1 infusion caused a stable reduction of blood pressure; the resting afferent nerve discharge rate began first to decrease but then recovered control mean values. SIN-1 infusion abolished the activation of group IV afferents after MS. This study indicates that endogenous NO production in a resting or contracting muscle attenuates the baseline activity of group IV muscle afferents and their activation after repetitive muscle contractions.